Omeprazole is a substituted benzimidazole, 5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl]-1H-benzimidazole, that inhibits gastric acid secretion. Omeprazole belongs to a class of antisecretory compounds, the substituted benzimidazoles, that do not exhibit anti-cholinergic or H2 histamine antagonist properties. Drugs of this class suppress gastric acid secretion by the specific inhibition of the H+/K+ ATPase enzyme system at the secretory surface of the gastric parietal cell.
Typically, omeprazole in the form of a delayed-release capsule, is prescribed for short-term treatment of active duodenal ulcers, gastric ulcers, gastroesophageal reflux disease (GERD), severe erosive esophagitis, poorly responsive systematic GERD, and pathological hypersecretory conditions such as Zollinger Ellison syndrome. These conditions are caused by an imbalance between acid and pepsin production, called aggressive factors, and mucous, bicarbonate, and prostaglandin production, called defensive factors.
These above-listed conditions commonly arise in healthy or critically ill patients and may be accompanied by significant upper gastrointestinal bleeding. H2 antagonists, antacids, and sucralfate are commonly administered to minimize the pain and the complications related to these conditions. These drugs have certain disadvantages associated with their use. Some of these drugs are not completely effective in the treatment of the aforementioned conditions and/or produce adverse side effects, such as mental confusion, constipation, diarrhea, thrombocytopenia, (lowered platelet count) and/or are relatively costly modes of therapy as they require the use of automated infusion pumps for continuous intravenous delivery.
Patients with significant physiologic stress are at risk for stress-related gastric mucosal damage and subsequent upper gastrointestinal bleeding (Marrone and Silen, 1984). Risk factors that have been clearly associated with the development of stress-related mucosal damage are mechanical ventilation, coagulopathy, extensive burns, head injury, and organ transplant (Zinner et al., 1981; Larson et al., 1984; Czaja et al., 1974; Skillman et al., 1969; and Cook et al., 1994). One or more of these factors are often found in critically ill, intensive care unit patients. A recent cohort study challenges other risk factors previously identified such as acid-base disorders, multiple trauma, significant hypertension, major surgery, multiple operative procedures, acute renal failure, sepsis, and coma (Cook et al., 1994). Regardless of the risk type, stress-related mucosal damage results in significant morbidity and mortality. Clinically significant bleeding occurs in at least twenty percent of patients with one or more risk factors who are left untreated (Martin et al., 1993). Of those who bleed, approximately ten percent require surgery (usually gastrectomy) with a reported mortality of thirty percent to fifty percent (Czaja et al., 1974; Peura and Johnson, 1985). Those who do not need surgery often require multiple transfusions and prolonged hospitalization. Prevention of stress-related upper gastrointestinal bleeding is an important clinical goal.
In addition to general supportive care, the use of drugs to prevent stress-related mucosal damage is considered by many to be the standard of care (AMA Drug Evaluations). However, general consensus is lacking about which drugs to use in this setting (Martin et al., 1993; Gafter et al., 1989; Martin et al., 1992). In two recent meta-analyses (Cook et al., 1991; Tryba, 1994), antacids, sucralfate, and H2-antagonists were all found to be superior to placebo and similar to one another in preventing upper gastrointestinal bleeding. Yet, prophylactic agents are withdrawn in fifteen to twenty percent of patients in which they are employed because of failure to prevent bleeding, or control pH (Ostro et al., 1985; Siepler, 1986; Ballesteros et al., 1990), or because of adverse effects (Gafter et al., 1989; Sax, 1987; Vial et al., 1991; Cantu and Korek, 1991; Spychal and Wickham, 1985). In addition, the characteristics of an ideal agent for the prophylaxis of stress gastritis and concluded that none of the agents currently in use fulfill their criteria (Smythe and Zarowitz, 1994).
Omeprazole reduces gastric acid production by irreversibly inhibiting the H+/K+ ATPase of the parietal cell—the final common pathway for gastric acid secretion (Fellenius et al., 1981; Wallmark et al., 1985; Frylund et al., 1988). Because this drug maintains gastric pH control throughout the dosing interval and has a very good safety profile, it is a logical choice for stress ulcer prophylaxis. The absence of an intravenous or oral liquid dosage form in the United States, however, has limited the testing and use of omeprazole in the critical care patient population. Subsequently, Barie et al (Barie and Hariri, 1992) described the use of omeprazole enteric-coated pellets administered through a nasogastric tube to control gastrointestinal hemorrhage in a critical care patient with multi-organ failure.
Stress ulcer prophylaxis has become routine therapy in intensive care units in most hospitals (Fabian et al, 1993.; Cook et al., 1991). Controversy remains regarding pharmacologic intervention to prevent stress-related bleeding in critical care patients. It has been suggested that the incidence and risk of gastrointestinal bleeding has decreased in the last ten years and drug therapy may no longer be needed (Cook et al., 1994; Tryba, 1994; Schepp, 1993). This reasoning is not supported by a recent placebo-controlled study. Martin et al. conducted a prospective, randomized, double-blind, placebo-controlled comparison of continuous-infusion cimetidine and placebo for the prophylaxis of stress-related mucosal damage (Marten et al., 1993). The study was terminated early because of excessive bleeding-related mortality in the placebo group. It appears that the natural course of stress-related mucosal damage in a patient at risk who receives no prophylaxis remains significant. In the placebo group, thirty-three percent of patients developed clinically significant bleeding, nine percent required transfusion, and six percent died due to bleeding-related complications. In comparison, fourteen percent of cimetidine-treated patients developed clinically significant bleeding, six percent required transfusions, and 1.5% died due to bleeding-related complication; the difference in bleeding rates between treatment groups was statistically significant. This study clearly demonstrated that continuous-infusion cimetidine reduced morbidity in critical care patients. Although, these data were used to support the approval of continuous-infusion cimetidine by the Food and Drug Administration for stress ulcer prophylaxis, H2-antagonists fall short of being the optimal pharmacotherapeutic agents for preventing of stress-related mucosal bleeding.
Another controversy surrounding stress ulcer prophylaxis is which drug to use. In addition to the various H2-antagonists, antacids and sucralfate are other treatment options for the prophylaxis of stress-related mucosal damage. An ideal drug in this setting should possess the following characteristics: prevent stress ulcers and their complications, be devoid of toxicity, lack drug interactions, be selective, have minimal associated costs (such as personnel time and materials), and be easy to administer (Smythe and Zarowitz, 1994).
Some have suggested that sucralfate is possibly the ideal agent for stress ulcer prophylaxis (Smythe and Zarowitz, 1994). Randomized, controlled studies support the use of sucralfate (Borrero et al., 1986; Tryba, 1987; Cioffi et al., 1994; Driks et al., 1987), but data on critical care patients with head injury, trauma, or burns are limited. In addition, a recent study comparing sucralfate and cimetidine plus antacids for stress ulcer prophylaxis reported clinically significant bleeding in three of forty-eight (6%) sucralfate-treated patients, one of whom required a gastrectomy (Cioffi et al., 1994). In the study performed by Driks and coworkers that compared sucralfate to conventional therapy (H2-antagonists, antacids, or H2-antagonists plus antacids), the only patient whose death was attributed to stress-related upper gastrointestinal bleeding was in the sucralfate arm (Driks et al., 1987).
H2-antagonists fulfill many of the criteria for an ideal stress ulcer prophylaxis drug. Yet, clinically significant bleeds can occur during H2-antagonist prophylaxis (Martin et al., 1993; Cook et al., 1991; Schuman et al., 1987) and adverse events are not uncommon in the critical care population (Gafter et al., 1989; Sax, 1987, Vial et al., 1991; Cantu and Korek, 1991; Spychal and Wickham, 1985). One reason proposed for the therapeutic H2-antagonist failures is lack of pH control throughout the treatment period (Ostro et al., 1985). Although the precise pathophysiologic mechanism(s) involved in stress ulceration are not clearly established, the high concentration of hydrogen ions in the mucosa (Fiddian-Green et al., 1987) or gastric fluid in contact with mucosal cells appears to be an important factor. A gastric pH >3.5 has been associated with a lower incidence of stress-related mucosal damage and bleeding (Larson et al., 1984; Skillman et al., 1969; Skillman et al., 1970; Priebe and Skillman, 1981). Several studies have shown that H2-antagonists, even in maximal doses, do not reliably or continuously increase intragastric pH above commonly targeted levels (3.5 to 4.5). This is true especially when used in fixed-dose bolus regimens (Ostro, 1985; Siepler, 1986; Ballesteros et al., 1990). In addition, gastric pH levels tend to trend downward with time when using a continuous-infusion of H2-antagonists, which may be the result of tachyphylaxis (Ostro et al., 1985; Wilder-Smith and Merki, 1992).
Because stress ulcer prophylaxis is frequently employed in the intensive care unit, it is essential from both a clinical and economic standpoint to optimize the pharmacotherapeutic approach. In an attempt to identify optimal therapy, cost of care becomes an issue. All treatment costs should be considered, including the costs of treatment failures and drug-related adverse events. While the actual number of failures resulting in mortality is low, morbidity (e.g., bleeding that requires blood transfusion) can be high, even though its association with the failure of a specific drug is often unrecognized.
Omeprazole represents an advantageous alternative to the use of H2 antagonists, antacids, and sucralfate as a treatment for complications related to stress-related mucosal damage. However, in its current form (capsules containing an enteric-coated granule formulation of omeprazole), omeprazole can be difficult or impossible to administer to patients who are unable (critically ill patients, children, elderly, patients suffering from dysphagia) or patients who are either unwilling or unable to swallow tablets or capsules. Therefore, it would be desirable to formulate an omeprazole solution which can be enterally delivered to a patient thereby providing the benefits of omeprazole without the drawbacks of the current capsule dose form.
Omeprazole has been formulated in many different embodiments such as in a mixture of polyethylene glycols formed a mixture of adeps solidus and sodium lauryl sulfate in a soluble, basic amino acid to yield a formulation designed for administration in the rectum as shown in U.S. Pat. No. 5,219,870 to Kim. U.S. Pat No. 5,395,323 to Berglund ('323) discloses a device for mixing a pharmaceutical from a solid supply into a parenterally acceptable liquid form for parenteral administration to a patient. The '323 patent teaches the use of an omeprazole tablet which is placed in the device and dissolved by normal saline, and infused into the patient. This device and method of infusing omeprazole does not provide the omeprazole solution as an enteral product nor is this omeprazole solution directly administered to the diseased or affected areas, namely the stomach and upper gastrointestinal tract, nor does this omeprazole formulation provide the immediate anti-acid effect of the present formulation.
U.S. Pat. No. 4,786,505 to Lovgren et al., discloses a pharmaceutical preparation containing omeprazole together with an alkaline reacting compound or an alkaline salt of omeprazole optionally together with an alkaline compound as a core material in a tablet formulation. The use of the alkaline material, which can be chosen from such substances as the sodium salt of carbonic acid, are used to form a “micro-pH” around each omeprazole particle to protect the omeprazole which is highly sensitive to acid pH. The powder mixture is then formulated to small beads, pellets, tablets and may be loaded into capsules by conventional pharmaceutical procedures.
This formulation of omeprazole does not provide an omeprazole dose form which can be enterally administered to a patient who may be unable and/or unwilling to swallow capsules or pellets nor does it teach a convenient form which can be used to make an omeprazole solution.
Several buffered omeprazole solutions have been disclosed. Andersson et al., 1993; Landahl et al., 1992; Andersson et al., 1990; Regardh et al., 1990; Andersson et al., 1990; Pilbrant et al., 1985.
All of the buffered omeprazole solutions described in these references were administered orally and were given to healthy subjects who were able to ingest the oral dose. In all of these studies, omeprazole was suspended in a solution including sodium bicarbonate, as a pH buffer, in order to protect the acid sensitive omeprazole during administration.
In all of these studies, repeated administration of sodium bicarbonate both prior to, during, and following omeprazole administration were required in order to prevent acid degradation of the omeprazole given via the oral route of administration. As a result, the ingestion of the large amounts of sodium bicarbonate and large volumes of water were required. In the above-cited studies, as much as 48 mmoles of sodium bicarbonate in 300 ml of water must be ingested for a single dose of omeprazole to be orally administered.
Initial reports of increased frequency of pneumonia in patients receiving stress ulcer prophylaxis with agents that raise gastric pH has influenced the pharmacotherapeutic approach to management of critical care patients. However, several recent studies (Simms et al., 1991; Pickworth et al., 1993; Ryan et al., 1993; Fabian et al., 1993), a meta-analysis (Cook et al., 1991), and a closer examination of the studies that initiated the elevated pH-associated pneumonia hypotheses (Schepp, 1993) cast doubt on a causal relationship. The relationship between pneumonia and antacid therapy is much stronger than for H2-antagonists. The shared effect of antacids and H2-antagonists on gastric pH seems an irresistible common cause explanation for nosocomial pneumonia observed during stress ulcer prophylaxis. However, there are important differences between these agents that are not often emphasized (Laggner et al., 1989). When antacids are exclusively used to control pH in the prophylaxis of stress-related upper gastrointestinal bleeding, large volumes are needed. Volume, with or without subsequent reflux, may be the underlying mechanism(s) promoting the development of pneumonia in susceptible patient populations rather than the increased gastric pH. The rate of pneumonia in our study (12%) was not unexpected in this critical care population and compares with sucralfate, which does not significantly raise gastric pH (Pickworth et al., 1993; Ryan et al., 1993).
The buffered omeprazole solutions of the above cited prior art require large amounts of sodium bicarbonate to be given by repeated administration. This is necessary to prevent acid degradation of the omeprazole. The administration of large amounts of sodium bicarbonate can produce at least four significant adverse effects which can dramatically reduce the efficacy of the omeprazole in patients and reduce the overall health of the patients. In the above-cited studies, basically healthy volunteers rather than sick patients were given only one or two dosages of omeprazole utilizing pre-dosing and post-dosing with large volumes of sodium bicarbonate. This dosing protocol would not be suitable for sick or critically ill patients who must receive multiple doses of omeprazole.
Since bicarbonate is usually neutralized in the stomach or is absorbed, such that belching results, patients with gastroesophageal reflux may exacerbate or worsen their gastroesophageal reflux disease as the belching can cause upward movement of stomach acid (Brunton, 1990).
Patients with conditions, such as hypertension or heart failure, are standardly advised to avoid the intake of excessive sodium as this can cause aggravation or exacerbation of their hypertensive conditions (Brunton, 1990).
Additionally, patients with numerous conditions which typically accompany critical illness should avoid the intake of excessive sodium bicarbonate as it can cause metabolic alkalosis which can result in a serious worsening of the patient's condition. Furthermore, excessive antacid intake (such as sodium bicarbonate) can result in drug interactions which produce serious adverse effects. For example, by altering gastric and urinary pH, antacids can alter rates of drug dissolution and absorption, bioavailability, and renal elimination (Brunton, 1990).
Since buffered omeprazole solution requires prolonged administration of the antacid, sodium bicarbonate, it makes it difficult for patients to comply with the above recommendation.
In addition to the disadvantages associated with excessive intake of sodium bicarbonate, the above-cited prior art teaches a relatively complex regimen for the oral administration of omeprazole. For example, in the Pilbrant et al. (1985) reference, the oral omeprazole administration protocol calls for administering to a subject who has been fasting for at least ten hours, a solution of 8 mmoles of sodium bicarbonate in 50 ml of water. Five minutes later, the subject ingests a suspension of 60 mg of omeprazole in 50 ml of water which also contains 8 mmoles of sodium bicarbonate. This is rinsed down with another 50 ml of 8 mmoles sodium bicarbonate solution. Ten minutes after the ingestion of the omeprazole dose, the subject ingests 50 ml of bicarbonate solution (8 mmoles). This is repeated at twenty minutes and thirty minutes post omeprazole dosing to yield a total of 48 mmoles of sodium bicarbonate and 300 ml of water in total which are ingested by the subject for a single omeprazole dose.
Not only does this regimen require the ingestion of excessive amounts of bicarbonate and water, it is unlikely that a healthy patient would comply with this regimen for each dose of omeprazole over the course of a prescribed omeprazole protocol. It is unlikely or even improbable that a critically ill patient would be able to comply with this regimen.
Even in healthy patients, the complexity of the drug regimen leads to the conclusion that patients would be unlikely to comply with this regimen thereby leading to a lack of beneficial outcome for the patient. It is well documented that patients who are required to follow complex schedules for drug administration are non-compliant and, thus, the efficacy of the buffered omeprazole solutions of the prior art would be expected to be reduced due to non-compliance. Compliance has been found to be markedly reduced when patients are required to deviate from a schedule of one or two (usually morning and night) doses of a medication per day. The use of the prior art buffered omeprazole solutions which require administration protocols with numerous steps, different drugs (sodium bicarbonate+omeprazole+PEG400 versus sodium bicarbonate alone), and specific time allotments between each stage of the total omeprazole regimen in order to achieve efficacious results is clearly in contrast with both current drug compliance theories and human nature.
The prior art (Pilbrant et al., 1985) teaches that the buffered omeprazole suspension can be stored at refrigerator temperatures for a week and deep frozen for a year while still maintaining 99% of their initial potency. It would be desirable to have an omeprazole solution which could be stored at room temperature or in a refrigerator for periods of time which exceed those of the prior art while still maintaining 99% of the initial potency. Additionally, it would be advantageous to have a form of the omeprazole and bicarbonate which can be utilized to instantly make the omeprazole solution/suspension of the present invention which is supplied in a solid form which imparts the advantages of improved shelf-life at room temperature, lower cost to produce, less expensive shipping costs, and which is less expensive to store.
It would, therefore, be desirable to have an omeprazole formulation which provides a cost effective means for the treatment of the aforementioned conditions without the adverse effect profile of H2 receptor antagonist, antacids, and sucralfate. Further, it would be desirable to have an omeprazole formulation which is convenient to prepare and administer to patients unable ingest capsules, which is rapidly absorbed, can be enterally delivered directly to the desired treatment region, which does not clog indwelling tubes, such as nasogastric tubes or other similar tubes, and which acts as an antacid immediately upon delivery. Furthermore, it would be desirable to have a pharmaceutical composition which is highly efficacious for the treatment of the aforementioned conditions.
The present invention provides a solution/suspension of omeprazole, lansoprazole or other suitable benzimidazoles which is suitable for enteral administration which includes all of the aforementioned advantages.